Recent studies have highlighted the significance of Fc-FcR interactions to achieve in vivo protection for neutralizing antibodies to HIV and other viruses or bacterial toxins through mechanisms including ADCC and ADCVl. We have defined both the amino acid and glycan requirements for IgG Fc binding to Fc?Rs and developed animal models based on novel strains of Fc?R humanized mice to determine the impact of amino acid and glycan modifications of human IgGs on their in vivo function. Despite the growing appreciation for the importance of Fc mediated effector functions to the in vivo potency of antibody mediated viral neutralization for bNAbs to HIV, no systematic studies have been performed to determine the optimal Fc structure that will result in these activities. We will characterize the contributions of Fc structure and effector functions to the activities of the bNAbs isolated by Nussenzweig and generate modified bNAbs optimized for Fc effector functions. These re-engineered bNAbs will be tested in vitro for neutralization, ADCC and ADCVBI and, in collaboration with Nussenzweig, in a novel in vivo neutralization assay, based on the TZM-bl assay in mice that carry human Fc?R. In collaboration with Bjorkman we will obtain structural information for these modified antibody Fc's, alone and in complex to specific Fc?Rs, These data will direct the generation of additional variants to further enhance Fc-Fc?R function. These studies will result in the generation of novel, bNAbs optimized for both neutralization and effector function and provide the framework to develop immunization strategies that will result in bNAbs with optimal effector properties.

Public Health Relevance

The generation of effective anti-HIV immunity remains a formidable challenge to global health. Through the studies proposed in this subproject we will investigate mechanisms to enhance immunogenicity of potential target antigens to generate neutralizing antibodies and to engineer neutralizing antibodies to augment their in vivo activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI100148-05
Application #
9208096
Study Section
Special Emphasis Panel (ZAI1-RRS-A)
Project Start
Project End
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
5
Fiscal Year
2017
Total Cost
$508,500
Indirect Cost
Name
California Institute of Technology
Department
Type
Domestic Higher Education
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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Bournazos, Stylianos; Wang, Taia T; Dahan, Rony et al. (2017) Signaling by Antibodies: Recent Progress. Annu Rev Immunol 35:285-311
Halper-Stromberg, Ariel; Nussenzweig, Michel C (2016) Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest 126:415-23
McGuire, Andrew T; Gray, Matthew D; Dosenovic, Pia et al. (2016) Specifically modified Env immunogens activate B-cell precursors of broadly neutralizing HIV-1 antibodies in transgenic mice. Nat Commun 7:10618
Ahmed, Alysia A; Keremane, Sravya R; Vielmetter, Jost et al. (2016) Structural characterization of GASDALIE Fc bound to the activating Fc receptor Fc?RIIIa. J Struct Biol 194:78-89

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